3-hydroxy-10, 13, 14, 15b-tetramethyl-1, 2, 3, 4, 4a, 5, 6, 6a, 6b, 7, 14, 15a, 15b-tetradecahydro-15h-naphth[2&#39;, 1&#39;:1, 2]-indeno[5, 6-b]indolizine, its esters, and intermediates thereto



United States Patent 3 HYDRQXY 10,13,14,15b TETRAMETHYL 1,2,

3,4,4a,5,6,6a,6b,7,14,15a,15b TETRADECAHYDRO- H NAPHTH[2,1':1,2] INDENO[5,6-b]lNDOLI- ZlNE, ITS ESTERS, AND INTERMEDIATES THERETO William F. Johns, Morton Grove, and Ivar Laos, Skokie, Ill., assignors to G. D. Searle & Co., Chicago, 111., a corporation of Delaware No Drawing. Filed July 30, 1964, Ser. No. 386,395

7 Claims. (Cl. 260295) The application for Letters Patent securing the invention herein described and claimed is a continuation-inpart of applicants prior copending application, Serial No. 277,454 filed May 2, 1963.

This invention relates to certain naphthindenoindolizines, intermediates thereto, and processes for the manufacture thereof. More particularly, this invention provides new and useful chemical compounds of the formula in which R represents hydrogen or an alkanoyl radical.

Among the alkanoyl radicals represented by R, especially lower alkanoyl radicals are preferred, i.e., radicals of the formula l --C-lower alkyl the lower alkyl constituent being methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, isohexyl, heptyl, or like monovalent, acyclic, straightor branched-chain, saturated, hydrocarbon groupings of the formula wherein n represents a positive integer less than 8.

The naphthindenoindolizines to which this invention relates are useful by reason of their valuable pharmacological properties. Thus, for example they counteract edematous swelling characteristic of the inflammatory response to tissue insult.

Manufacture of the subject compounds proceeds by hydrogenating the endocyclic double bond in 3,8-acetoxy- 17a-methyl-5u,22li-D-homo-C-nor-l8-norspirost-l7 (1711)- en, [Compound IX in J. Amer. Chem. Soc., 76, 4013 (1954)] over rhodium-on-alumina catalyst to give 35- acetoxy 17afi methyl 504,22fi-D-h0l'110-C-I10f-18-1101- spirosten, cleaving Ring F therein by heating with octanoic acid and acetic anhydride to give SB-acetoxy- 17afi methyl 26-octanoyloxy-5a,22,8-D-homo-C-nor-18- norfurost-(22)-en, cleaving Ring E therein by cold oxidation with chromium trioxide and acetic acid to give 3,8 acetoxy 17fi-acetyl-Hap-methyl-l6fi-(4-rnethyl-5- octanoyloxyvaleryloxy) 50c D-homo-C-nor-18-norandrostane, saponifying the ester groups therein by heating with aqueous potassium hydroxide in tert-butanol to give 17 acetyl-l7aB-methyl-5a-D-homo-C-nor-18-norandrost-16-en-3B-ol, and esterifying the 3-alcohol function therein by heating with acetic anhydride and pyridine to give 35 acetoxy 17-acetyl-17aB-methyl-5a-D-homo- C-nor-l8-norandrost-l6-ene. This compound is mixed with cold 6-(3-picolyl)-lithium and the resultant organometallic adduct hydrolyzed to 3 8-acetoxy-l7-(a-hydroxy- [1,5 dirnethyl 2 pyridylmethyl) 17a-m6tl1Yl-5a-D- homo-C-nor-18-norandrost-16-en (a reesterification procedure being included in the work-up to restore the 3- ester group at least partially removed in process) which, in turn, is consecutively brominated with phosphorus tribromide and cyclized with triethylamine to give 3- acetoxy 10,13,14,15b tetr'amethyl 1,2,3,4,4a,5,6,6a,6b, 7,14,14a,15a,15b tetradecahydro 15H-naphth[2,1:l, 2]-indeno[5,6-b]indolizine, a preferred embodiment of the instant invention. The 3-ester group therein can be saponified by heating with aqueous methanolic potassium carbonate and the resultant alcohol re-esterified ad libitum by heating with a selected alkanoic acid anhydride and pyridine.

The following examples describe in detail compounds illustrative of the present invention and methods which have been devised for their manufacture. However, the invention is not to be construed as limited thereby, either in spirit or in scope, since it will be apparent to those skilled in the art of organic synthesis that many modifications, both of materials and of methods, may be practiced without departing from the purpose and intent of this disclosure. Throughout the examples hereinafter set forth, temperatures are given in degrees Centigrade and relative amounts of materials in parts by weight, except as otherwise noted. Specific rotations are referred to the D line of sodium.

EXAMPLE 1 35-acetoxy-J 7aB-methyl-5u,22,8-D-h0m0-C-n0r-18 norspz'rostan.-A slurry of 25 parts of 5% rhodium-on-alumina in a solution of 200 parts of 3 fi-acetoxy-17a-methyl- 50:,22fi-D-h0II1O-C-I1Ol 18-norspirost-17(17a)-en in 900 parts of acetic acid is maintained with agitation under 3 atmospheres of hydrogen at 44 until hydrogen uptake indicates that reduction of the endocyclic double bond is complete (representatively, after 7 hours). Catalyst is thereupon filtered off and washed with benzene, and the benzene wash combined with the filtrate. Solvent is removed by vacuum distillation; and the residue is crystallized from a mixture of dichloromethane and methanol, using decolorizing charcoal in process. The material thus isolated in 3fi-acetoxy-l7aB-methyl-5a,22,8-D- homo-C-nor-18-norspirostan melting at 179-l81 and further characterized by a specific rotation of 12. The product has the formula CH3 CH3 CHaCOO- EXAMPLE 2 3/3-acet0xy-1 7aB-m ethyl 26 octtmoyloxy 5 0:,22 [-3 D- homo-C-nor-l8-n0rfur0st-20(22)-en.-A solution of 134 parts of 3fi-acetoxy-17aB-methyl-5u,22p-D-homo-C-norl8-norspirostan in 95 parts of octanoic acid and parts of acetic anhydride is heated to 240 during 15 minutes and maintained at 240-250 for 20 minutes, volatile components being allowed to distil the while. The resultant mixture is cooled to room temperature and diluted with 350 parts of ether and 200 parts of water, whereupon an excess of aqueous 10% potassium hydroxide is introduced and the mixture thus obtained maintained with vigorous agitation at room temperatures for 20 minutes. The organic phase is thereupon separated and consecutively washed with water, aqueous potassium hydroxide, and water, then stripped of solvent by vacuum distillation. The residue, a mobile oil, is 3,8-acetoxy-17aB-methyl-26-octa- 3 noyloxy-5a,22,6-D-homo-C-nor 18 norfurost-20(22)-en, having the formula CHsCO O- EXAMPLE 3 3B acetoxy 17;8-acetyl-17a,3-methyl-l6[3-(4-methyl-5- octanoy loxyvalery loxy) 5 a-D-homo-C-nor-I 8-n0randrostane.-To a solution of 167 parts of 3,8-acetoxy-17aflmethyl 26-octanoyloxy-5a,22/3D-homo-C-norl8-norfurost-20(22)-en in 1000 parts of acetic acid and 1200 parts of dichloroethane at 5 is added, with vigorous agitation during 20 minutes, a solution of 90 parts of chromium trioxide in 800 parts of aqueous 90% acetic acid. The resultant mixture is maintained with agitation at for 1 hour, at which point a solution of 100 parts of sodium bisulfite in 400 parts of water is mixed in, followed by 1000 parts of water. The mixture thus obtained is extracted with ether. The ether extract is washed with water and stripped of solvent by distillation at temperatures less than 60. The residue is taken up in ether, the ether solution is filtered, and the filtrate is Washed with aqueous potassium bicarbonate and thereupon stripped of solvent by vacuum distillation. The residue, a mobile oil, is 3B-acetoxy-17fi-acetyl-17aB-methyl-16(3- (4 methyl-5-octanoyloxyvaleryloxy)-5a-D-homo-C-nor- 18-norandrostane, having the formula COCHB HaC CHaCOO EXAMPLE 4 17 acetyl 17aB-methyl-5ot-D-h0m0-C-n0rJ8-n0randrost-16-en-3,8-0l.A solution of 174 parts of 3/3-acetoxy- 17f? acetyl 17a,8-methyl-16B-(4-methyl-5-octanoyloxyvaleryloxy)-5ot-D-homoC-nor-18-norandrostane in 1015 parts of tert-butyl alcohol and 600 parts of aqueous 20% potassium hydroxide is heated at the boiling point under reflux with agitation in a nitrogen atmosphere for 90 minutes. The tert-butyl alcohol is thereupon distilled off and the distilland partitioned between Water and ether. The ethereal phase is concentrated by distillation to the point of incipient crystallizatiom then set aside at room temperatures until crystallization is complete. The product thrown down, filtered oil and recrystallized from a mixture of acetone and petroleum ether, is 17-acetyl- 17ai3 methyl-Su-D-homQ-C-nOr-I8-norandrost-16-en-3fl ol melting at l75178 and further characterized by a specific rotation of +54. The product has the formula COCHa EXAMPLE 5 3B acetoxy-J 7 -acetyl-1 7aB-methyl-5 ot-D-homo-c-norl8-norandrost-16-ene.-A solution of approximately 30 COCH3 H3O I l CHsCOO- EXAMPLE 6 3/3 -acet0xy-17-(a-hydroxy-a,S-dimthyl-Z-pyridylmethyl) 17a methyl 5ot-D-homo-C-nor-l8-norandr0st-16- ene.-An n-butylithium solution prepared from 6 parts of lithium and 67 parts of n-butyl bromide in a total of 525 parts of anhydrous ether is cooled to 40 and maintained thereat while a solution of approximately 76 parts of 2-bromo-5-methy1pyridine in 630 parts of anhydrous ether is mixed in during 20 minutes. The resultant redbrown solution is stirred 5 minutes, whereupon a solution of 36 parts of 3,8-acetoxy-l7-acety1-l7afi-methyl-5u- D-homo-C-nor-l8-norandrost-l6-ene in 875 parts of ether is mixed in during 15 minutes, temperature being held at -40 throughout. Discoloration and formation of a whitish precipitate occurs. The reaction mixture is stirred for 1 hours while the temperature rises to -5, whereupon the mixture is allowed to stand overnight at room temperatures. The ether phase is separated, Washed to neutrality with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residual oil is chromatographed on silica gel, using benzene and ethyl acetate as developing solvents. From an eluate comprising 10% ethyl acetate in benzene, on distillation of solvent, is obtained a residue which is mixed with 225 parts of acetic anhydride and 300 parts of pyridine. The mixture is allowed to stand at room temperatures overnight, then poured into 5 volumes of water. The mixture thus obtained is extracted with ether. The ether extract is washed with Water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residue, further purified by chromatography on silica gel (again using benzene and ethyl acetate as developing solvents), is 3,8-acetoxy-17-(u-hydroxya,5 dimethyl 2-pyridylmethyl)-17a-methy15a-D-homo- 3-acet0xy-10,13,14,15b tetramethyl 1,2,3,4,4a,5,6,6a, 6b,7,14,14a,15a,15b tetradecahydro 15H-naphth-[2,1': 1,2]indeno[5,6-b]ind0lizine.-To a solution of approximately 3 parts of 3,8-acet0xy-17-(a-hydroxy-aj-dimethyl- Z-pyr-idylmethyl) Hot-methyl 50c D-homo-C-nor-18- norandrost-16-ene in 65 parts of dichloromethane at around 5 is added approximately 2 parts of phosphorus. tribromide. The resultant mixture is maintained with CHaCOO agitation in a closed vessel for approximately 20 minutes, then allowed to stand at 3 overnight. Solvent is evap orated under nitrogen at temperatures of the order of and to the cold semi-crystalline residue is added a solution of 3 parts of triethylamiue in 40 parts of methanol. The mixture thus obtained is maintained with agitation in a closed vessel with vigorous agitation at 05 for approximately 4 hours. A clear yellow solution forms, following which crystallization occurs. The solid prodnot is collected on a filter, washed with cold methanol, and dried in air to give 3-acetoxy-10,13,14,ISb-tetramethyl-1,2,3,4,4a,5,6,6a,6b,7,14,14a,15a,15b tetradecahydro- 15H-naphth[2',l':1,2]indeno[5,6-b1indolizine melting at 184188. The product has the formula 0 H3 0 C 0 CH3 CH3 H30 H3O N EXAMPLE 8 3-hydr0xy-10,13,14,15b tetramethyl ],2,3,4,4a,5,6,6a, 6b,7,14,14a,15a,15b tetradecahydro 15H-naphth[2',1': 1,2]inden0[5,6-b]ind0lizine.A solution of 1 part of 3- acetoxy 10,13,14,15b tetramethyl 1,2,3,4,4a,5,6,6a,6b, 7,14,14a,15a,15b tetradecahydro 15H-naphth[2,1':1, 2]-indeno[5,6-b1indolizine in 70 parts of methanol and 6 parts of aqueous 10% potassium carbonate is heated at the boiling point under reflux for 1 hour, then cooled and diluted with 3 volumes of water. The precipitate which forms is filtered oflf, dried in air, and recrystallized from aqueous ethanol to give 3-hydroxy- 10,13,14,l5b tetramethyl- 1,2,3,4,4a,5,6,6a,6b,7,14,14a,15a,15b tetradeca- 6 hydro 15H naphth[2,l':1,2]indeno[5,6-b]indolizine, having the formula What is claimed is: 1. A compound of the formula CEa CIHa H2O HaC N wherein R represents a member of the group consisting of hydrogen and a radical of the formula 2. 3-acetoxy-10,13,14,15b tetramethyl 1,2,3,4,4a,5, 6,6a,6b,7,14,14a,15a,15b tetradecahydro ISH-naphth- [2,1: 1,2]indeno[5,6-b]indolizine.

3. 3-hydr0xy-10,13,14,15b tetramethyl 1,2,3,4,4a,5, 6,6a,6b,7,14,14a,l5a,15b tetradecahydro ISH-naphth- [2,1': 1,2]indeno [5,6-b]indolizine.

4. 3p3-acetoxy 17af3 methyl 5a,22fl-D-homo-C-nor- 18-norspirostan.

5. 17-acetyl 17afl methyl 5m D-homo-C-nor-18- norandrost-16-en-3fi-ol.

6. 3B-acetoxy 17 acetyl l7afl-methyl-5a-D-homo- C-nor-l8-norandrost-16-ene.

7. 3,8-acetoxy-17 (a-hydroxy a,5-dimethyl-2-pyridylmethyl) 17a-methy1- 5a-D-hom0-C-nor 18-norandrost- 16-ene.

No references cited.

WALTER A. MODANCE, Primary Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,228,951 January 11, 1966 William F. Johns et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

In the heading to the printed specification, line 3,

for "14,15a," read l4,l4a,l5a, column 1, line 50, and column 2, line 30, for "-17(l7d)-", each occurrence, read -17(l7a) column 2, line 40, for "in" read is column 4, line 72 and column 6, line 39, for "l7a", each occurrence, read 17a- Signed and sealed this 20th day of December 1966.

( Attest:

ERNEST W. SWIDER Attesting Officer EDWARD J. BRENNER Commissioner of Patents 

1. A COMPOUND OF THE FORMULA
 2. 3-ACETOXY-10, 13, 14, 15B-TETRAMETHYL-1,2,3,4,4A,5, 6,6A,6B,7,14,14A,15A,15B-TETRADECAHYDRO-15H-NAPHTH(2'',1'':1,2)INDENO(5,6 -B)INDOLIZINE. 